WO2007066845A1

WO2007066845A1 - Process for preparation of thiophenol derivatives

Info

Publication number: WO2007066845A1
Application number: PCT/KR2005/004361
Authority: WO
Inventors: Je-Sung Jee; Jae-Geun Lee; Yong-Jin Cho; Do-Hee Lee
Original assignee: Jmc Corporation
Priority date: 2005-12-05
Filing date: 2005-12-16
Publication date: 2007-06-14
Also published as: KR100697249B1

Abstract

Provided is a process for preparing thiophenol derivatives, using aromatic disulfide as a starting material, and inexpensive sodium bisulfite (NaHSO3) as a reducing agent. The process can be carried out on an industrial scale at low production costs, secures advantageous reaction conditions by using a small amount of water- soluble alcohol solvent. Further, the process can maximize the purity of the products by inhibiting reverse oxidation of the final product by the action of sulfur dioxide (SO2) produced during the preparation process, after solvent extraction of the starting materials present as impurities of the thiophenol derivatives.

Description

PROCESS FOR PREPARATION OF THIOPHENOL

DERIVATIVES

FIELD OF THE INVENTION

The present invention relates to a process for preparation of thiophenol derivatives. More specifically, the present invention relates to a process for preparation of thiophenol derivatives comprising reducing aromatic disulfide to prepare thiophenol derivatives, using sodium bisulfite (NaHSθ₃) as an inexpensive reducing agent. Therefore, the present invention enables production of the thiophenol derivatives with high yield and high purity on an industrial scale at low production costs. BACKGROUND OF THE INVENTION

Thiophenol derivatives represented by Formula I below have been widely used as intermediates of agrochemical and medicinal raw materials.

wherein X is selected from the group consisting of hydrogen, halogens (F, Cl and Br), amine and nitro. As known methods for preparing the thiophenol derivatives of Formula I, there are generally methods involving reduction of aromatic disulfide as a raw material, methods involving direct substitution of a halogenated aromatic compound with a metal salt of sulfur, and methods involving hydrolysis of aromatic halogenated methyl sulfide.

In the method for preparing the thiophenol derivatives via reduction of aromatic disulfide as a raw material, a zinc metal in an acetic acid solvent (US Patent No. 5,248,822), sodium borohydride in an aqueous base (US Patent No. 5,659,088), or sodium sulfide (US Patent No. 5,883,285) is used as the reducing agent. However, this method suffers from unfeasibility of industrial application and mass production, due to problems such as metal contamination and production of wastes, potential risk arising from evolution of hydrogen gas, and the like.

Meanwhile, in the method for preparing the thiophenol derivatives via direct substitution of a halogenated aromatic compound with a metal salt of sulfur, the substitution reaction is carried out using sodium sulfide (Na₂S) or sodium hydrogen sulfide (NaHS) as a nucleophilic agent (US Patent No. 3,931,321). However, this method may be susceptible to the occurrence of additional reduction reaction, due to reducing power of the metal salt of sulfur.

The method for preparing the thiophenol derivatives via hydrolysis of aromatic halogenated methyl sulfide (US Patent No. 5,932,731) has advantages capable of preparing various regioisomers of thiophenol derivatives, but suffers from a decrease in the price and cost competitiveness of products arising from an immense expenditure on facilities and equipment, because highly toxic chlorine must be employed to prepare the aromatic halogenated methyl sulfide as a starting material. SUMMARY OF THE INVENTION

Therefore, the inventors of the present invention have made a great deal of efforts and attempts to improve the price and cost competitiveness of products by production of thiophenol derivatives, using sodium bisulfite (NaHSO₃) which is an inexpensive reducing agent and can be produced on an industrial scale.

That is, as a result of a variety of extensive and intensive studies and experiments, the inventors of the present invention have discovered the facts that it is possible to produce high-purity products at a low production cost, by preparing metal salts of thiophenol derivatives, in the presence of an aqueous lower alcohol solution in order to enhance the reaction efficiency by increasing the solubility of the starting material, using an inexpensive aromatic disulfide prepared through a synthetic method domestically developed by the present inventors, as a starting material, and using sodium bisulfite (NaHSOa), which can be produced on an industrial scale at low production costs, as a reducing agent; recovering a water-soluble lower alcohol; and extracting and recovering the unreacted starting material using an aromatic hydrocarbon solvent or a halogenated hydrocarbon solvent. The present invention has been completed based on these findings.

Therefore, an object of the present invention is to provide a process for preparing thiophenol derivatives of Formula I with high yield and high purity on an industrial scale at low production costs.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS In accordance with an aspect of the present invention, the above and other objects can be accomplished by the provision of a process for preparation of thiophenol derivatives represented by Formula I:

wherein X is selected from the group consisting of hydrogen, halogens (F, Cl and Br), amine and nitro,

using aromatic disulfide as a starting material, the process comprising:

(a) preparing metal salts of thiophenol derivatives of Formula I by reducing aromatic disulfide with an aqueous base and sodium bisulfite (NaHSO₃), in the presence of an aqueous lower alcohol solution in order to enhance the reaction efficiency by increasing the solubility between an organic starting material and an inorganic reducing agent;

(b) extracting and recovering the aromatic disulfide impurities contained in the aqueous metal salt solution of the thiophenol derivatives, using an aromatic hydrocarbon solvent and/or a halogenated hydrocarbon solvent; and

(c) neutralizing the metal salts of thiophenol derivatives, from which the aromatic disulfide starting material impurities were removed, with an inorganic acid, extracting the thiophenol derivatives with the aromatic hydrocarbon solvent and/or the halogenated hydrocarbon solvent, and concentrating to recover the solvent.

As described above, the most significant characteristics of the present invention reside in that the thiophenol derivatives are prepared by 'reducing aromatic disulfide with economically inexpensive sodium bisulfite (NaHSO₃) under reaction conditions of the aqueous base and the aqueous lower alcohol solution.

In Step (a), sodium bisulfite may be used in the form of a 20 to 35% aqueous solution. If the concentration of the aqueous sodium bisulfite solution is excessively high, this may result in a decreased economic efficiency of the manufacturing process.

On the other hand, if the concentration of the aqueous sodium bisulfite solution is excessively low, this may undesirably result in a low reaction rate and production of large amounts of waste water. A mole ratio of sodium bisulfite to the aromatic disulfide may be preferably in a range of 1.1 to 1.5, particularly preferably in a range of 1.3 to 1.4.

Details of the aromatic disulfide and preparation thereof can be found in Korean Patent Application No. 2005-0117408, assigned to the present applicant, the disclosure of which is incorporated by reference herein in its entirety.

As the lower alcohol added to enhance the reaction efficiency by increasing the solubility of the starting material aromatic disulfide in the above-mentioned reduction reaction, ethanol, propanol, isopropanol, or the like, having a boiling point of 75 ^°C or higher, may be used. Particularly, isopropanol may be preferably used in an amount of 3 to 5 moles, relative to the aromatic disulfide.

Further, reduction of the aromatic disulfide may be carried out, for example, at a temperature of 75 ^°C to 80 ^°C . If the reduction temperature is excessively low, this may result in no progress of the reaction or an excessively low reaction rate, thereby decreasing an economic efficiency of the manufacturing process. On the other hand, if the reduction temperature is excessively high, this may undesirably result in decomposition of the products or increased risk of adverse side reactions. More preferably, the reduction reaction may be carried out at 80.3 ^°C, corresponding to an azeotropic point of isopropanol and water,. under atmospheric pressure conditions.

As the aromatic hydrocarbon solvent or halogenated hydrocarbon solvent added to extract the unreacted aromatic disulfides which are present as impurities of the thiophenol derivatives in Step (b), aromatic solvents such as benzene, toluene, xylene and monochlorobenzene, and halogenated solvents such as chloroform, dichloromethane and dichloroethane may be employed without being limited thereto.

As examples of the inorganic acid for neutralizing the metal salts of thiophenol derivatives in Step (c), mention may be made of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid. Preferably, the metal salts are neutralized to a range of pH 6.5 to 7.2, using hydrochloric acid. Where the acidity for neutralization is excessively low, this may result in problems associated with a necessity of an additional process to remove the acidity of a thiophenol derivative extraction solution. On the other hand, where the acidity for neutralization is excessively high, this may undesirably result in problems of a low production yield due to the residual metal salts of thiophenol derivatives.

Examples of the aromatic hydrocarbon solvent or the halogenated hydrocarbon solvent used as the extraction solvent of the thiophenol derivatives may include, but are not limited to, aromatic solvents such as benzene, toluene, xylene and monochlorobenzene, and halogenated solvents such as chloroform, dichloromethane and dichloroethane, similar to those in Step (b).

Sulfur dioxide (SO₂), produced by the neutralization of sodium bisulfite used in an excessive amount in neutralization of the metal salts of thiophenol derivatives with the inorganic acid, inhibits oxidation of the thiophenol derivatives into aromatic disulfides by the dissolved oxygen in the aqueous solution or by contact with the atmosphere, and it is therefore possible to obtain the thiophenol derivatives with high purity.

In the foregoing, unless otherwise particularly indicated, ranges for various reaction parameters such as reactant ratios, temperatures, pressure and the like mean the optimal conditions for carrying out the reactions in accordance with the present invention.

Hereinafter, an exemplary reaction for preparing the thiophenol derivatives in accordance with the present invention may be represented by Reaction Scheme 1 below.

[Reaction Scheme 1]

In Reaction Scheme 1, X is hydrogen, halogen, amine or nitro, M is Na or K, and R is ethyl or propyl.

EXAMPLES

Now, the present invention will be described in more detail with reference to the following examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention. Example 1: Preparation of 4-aminothiophenol

800.0 g of an aqueous 15% sodium hydroxide solution, 120.2 g of 99% isopropanol and 102.4 g of 95% 4,4'-diaminophenyldisulfide were added dropwise to 271.5 g of an aqueous 23% sodium bisulfite solution at an ambient temperature in one portion. The resulting mixture was warmed to 80 °C and stirred for 8 hours. As reduction reaction of 4,4'-diaminophenyldisulfide proceeds, a yellow color of 4,4'- diaminophenyldisulfide becomes pale.

Upon completion of the reduction reaction, isopropanol was removed by azeotropic distillation with water at 80.3 ^°C. When the temperature of the reaction solution was elevated to 100^°C or higher, azeotropic distillation of isopropanol was terminated. The reaction solution was cooled to 40 ^°C, and 37.2 g of 99% toluene was added dropwise to the reaction solution which was then stirred for 1 hour. This was followed by layer separation to extract and remove the unreacted 4,4'- diaminophenyldisulfide. 291.6 g of 35% hydrochloric acid was gradually added dropwise to an aqueous solution of a 4-aminothiophenol sodium salt at the same temperature to thereby adjust the pH of the solution to a value of 6.6. Thereafter, 37.2 g of 99% toluene was added to the solution which was then stirred for 30 min, followed by separation of a toluene layer containing 4-aminothiophenol dissolved therein.

24.8 g of water, from which dissolved oxygen was removed by nitrogen purge, was added dropwise to the thus-separated toluene layer which was then stirred for 30 min, followed by separation of a toluene layer. Water saturated in the thus-separated toluene layer was removed by azeotropic distillation of toluene in conjunction with reduced-pressure distillation. Upon complete distillation of toluene, nitrogen gas was charged to the resulting distillate to prevent air-induced oxidation, thereby obtaining 80.2 g (yield: 80%) of 99.9% 4-aminothiophenol. From analysis of the thus-obtained material, it was confirmed that the title compound was prepared.

Example 2: Preparation of 4-bromothiophenol

1000.3 g of an aqueous 15% sodium hydroxide solution, 151.8 g of 99% isopropanol and 190.0 g of 99% 4,4'-dibromophenyldisulfide were added dropwise to 339.4 g of an aqueous 23% sodium bisulfite solution at an ambient temperature in one portion. The resulting mixture was warmed to 80 ^"C and stirred for 6 hours.

Upon completion of the reduction reaction, isopropanol was removed by azeotropic distillation with water at 81 ^°C . When the temperature of the reaction solution was elevated to 100^°C or higher, azeotropic distillation of isopropanol was terminated. The reaction solution was cooled to 40⁰C, and 46.6 g of 99% toluene was added dropwise to the reaction solution which was then stirred for 1 hour. This was followed by layer separation to extract and remove the unreacted 4,4'-dibromophenyldisulfide. 364.7 g of 35% hydrochloric acid was gradually added dropwise to an aqueous solution of a 4-bromothiophenol sodium salt at the same temperature to thereby adjust the pH of the solution to a value of 6.7. Thereafter, 42.5 g of 99% dichloromethane was added to the solution which was then stirred for 30 min, followed by separation of a dichloromethane layer containing 4-bromothiophenol dissolved therein.

24.8 g of water, from which dissolved oxygen was removed by nitrogen purge, was added dropwise to the thus-separated dichloromethane layer which was then stirred for 30 min, followed by separation of a dichloromethane layer. The thus-separated dichloromethane layer was completely distilled by reduced-pressure distillation, and nitrogen gas was charged to the resulting distillate to prevent air-induced oxidation, thereby obtaining 141.8 g (yield: 75%) of 99.5% 4-bromothiophenol. From analysis of the thus-obtained material, it was confirmed that the title compound was prepared.

INDUSTRIAL APPLICABILITY

As apparent from the above description, a process for preparation of thiophenol derivatives according to the present invention secures industrial-scale production at low costs by using sodium bisulfite as an inexpensive reducing agent, cheaper than reducing agents used in conventional preparation methods, and secures advantageous reaction conditions of heating/refluxing in an aqueous lower alcohol solution. Particularly, according to the process of the present invention, sulfur dioxide, produced during the preparation process, inhibits reverse oxidation of the final product thiophenol derivatives into aromatic disulfides which may occur in additional preparation processes, following the removal of the unreacted aromatic disulfides by solvent extraction. Therefore, the present invention can maximize the purity of the products and can be widely applied to various fields of fine chemistry.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

Claims

WHAT IS CLAIMED IS

1. A process for preparation of thiophenol derivatives represented by Formula I:

using aromatic disulfide as a starting material, and sodium bisulfite (NaHSOa) as a reducing agent, the process comprising:

(a) preparing metal salts of thiophenol derivatives of Formula I by reducing aromatic disulfide with an aqueous base and sodium bisulfite (NaHSOs), in the presence of an aqueous lower alcohol solution in order to enhance the reaction efficiency by increasing the solubility between an organic starting material and an inorganic reducing agent;

(b) extracting and recovering the aromatic disulfide impurities contained in the aqueous metal salt solution of thiophenol derivatives, using an aromatic hydrocarbon solvent and/or a halogenated hydrocarbon solvent; and

2. The process according to claim 1, further comprising, after Step (c), inhibiting oxidation of the thiophenol derivatives into aromatic disulfides via dissolved oxygen in the aqueous solution or via contact with the atmosphere, by the action of sulfur dioxide (SO₂) produced by the neutralization of sodium bisulfite used in an excessive amount in neutralization of the metal salts of thiophenol derivatives with the inorganic acid.

3. The process according to claim 1, wherein sodium bisulfite in Step (a) is a 20 to 35% aqueous solution thereof, and is used in the mole ratio range of 1.1 to 1.5, relative to the aromatic disulfide.

4. The process according to claim 1, wherein reduction of aromatic disulfide in Step (a) is carried out at a temperature of 75 ^°C to 80 ^°C under atmospheric pressure.

5. The process according to claim 1, wherein the lower alcohol in Step (a) is ethanol or propanol having a boiling point of 75 ^°C or higher.

6. The process according to claim 1, wherein the metal salts of thiophenol derivatives in Step (c) are neutralized to a range of pH 6.5 to 7.2, using the inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid.